Molecular Hybridization as a Tool for Designing Multitarget Drug Candidates for Complex Diseases

Current Topics in Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 19(19), P. 1694 - 1711

Published: June 26, 2019

Molecular hybridization is a well-exploited medicinal chemistry strategy that aims to combine two molecules (or parts of them) in new, single chemical entity. Recently, it has been recognized as an effective approach design ligands able modulate multiple targets interest. Hybrid compounds can be obtained by linking (presence linker) or framework integration (merging fusing) strategies. Although very promising combat the multifactorial nature complex diseases, development molecular hybrids faces critical issues selecting right target combination and achievement balanced activity towards them, while maintaining drug-like-properties. In this review, we present recent case histories from our own research group demonstrate why how carried out address challenges multitarget drug discovery therapeutic areas are Alzheimer's parasitic diseases. Selected examples spanning linker- fragment- based will allow discuss consequences relevant design.

Language: Английский

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Antileishmanial Activity of Dimeric Flavonoids Isolated from Arrabidaea brachypoda

Molecules, Journal Year: 2018, Volume and Issue: 24(1), P. 1 - 1

Published: Dec. 20, 2018

Leishmaniasis are diseases caused by parasites belonging to Leishmania genus. The treatment with pentavalent antimonials present high toxicity. Secondary line drugs, such as amphotericin B and miltefosine also have a narrow therapeutic index. Therefore, there is an urgent need develop new drugs treat leishmaniasis. Here, we the in vitro anti-leishmanial activity of unusual dimeric flavonoids purified from Arrabidaea brachypoda. Three compounds were tested against Leishmana sp. Compound 2 was most active promastigotes. Quantifying infected macrophages revealed that compound intracellular amastigotes L. amazonensis, without displaying host cell Drug combinations presented additive effect, suggesting absence interaction between 2. Amastigotes treated demonstrated alterations Golgi accumulation vesicles inside flagellar pocket. 2-treated cytoplasmic myelin-like structure. When administered amazonensis-infected mice, neither oral nor topical treatments effective parasite. Based on activity, can be used lead structure for development molecules could useful structure-active studies Leishmania.

Language: Английский

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The application of isatin-based multicomponent-reactions in the quest for new bioactive and druglike molecules

European Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 211, P. 113102 - 113102

Published: Dec. 18, 2020

Language: Английский

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The current drug discovery landscape for trypanosomiasis and leishmaniasis: Challenges and strategies to identify drug targets

Drug Development Research, Journal Year: 2020, Volume and Issue: 83(2), P. 225 - 252

Published: April 6, 2020

Abstract Human trypanosomiasis and leishmaniasis are vector‐borne neglected tropical diseases caused by infection with the protozoan parasites Trypanosoma spp. Leishmania spp., respectively. Once restricted to endemic areas, these now distributed worldwide due human migration, climate change, anthropogenic disturbance, causing significant health economic burden globally. The current chemotherapy used treat has limited efficacy, drug resistance is spreading. Hence, new drugs urgently needed. Phenotypic compound screenings have prevailed as leading method discover candidates against diseases. However, publication of complete genome sequences multiple strains, advances in application CRISPR/Cas9 technology, vivo bioluminescence‐based imaging set stage for advancing target‐based discovery. This review analyses limitations narrow pool available presently treating It describes drug‐based clinical trials highlighting most promising leads. Furthermore, presents a focused discussion on important biological pharmacological challenges that discovery programs must overcome advance candidates. Finally, it examines advantages modern research tools designed identify validate essential genes targets, including genomic editing applications imaging.

Language: Английский

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Genomic Insight of Leishmania Parasite: In-Depth Review of Drug Resistance Mechanisms and Genetic Mutations

ACS Omega, Journal Year: 2024, Volume and Issue: unknown

Published: March 8, 2024

Leishmaniasis, which is caused by a parasitic protozoan of the genus Leishmania, still major threat to global health, impacting millions individuals worldwide in endemic areas. Chemotherapy has been principal method for managing leishmaniasis; nevertheless, evolution drug resistance offers significant obstacle therapeutic success. Drug-resistant behavior these parasites complex phenomenon including both innate and acquired mechanisms. Resistance frequently related changes transportation, target alterations, enhanced efflux from pathogen. This review revealed specific genetic mutations Leishmania that are associated with commonly used antileishmanial drugs such as pentavalent antimonials, miltefosine, amphotericin B, paromomycin, resulting gene expression along functioning various proteins involved uptake, metabolism, efflux. Understanding linked essential creating approaches tackling avoiding spread drug-resistant variants. Based on treatments focus pathways could potentially improve treatment efficacy help long-term leishmaniasis control. More study needed uncover complete range generating medication develop new therapies based available information.

Language: Английский

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4-Aminoquinoline as a privileged scaffold for the design of leishmanicidal agents: structure–property relationships and key biological targets

Frontiers in Chemistry, Journal Year: 2025, Volume and Issue: 12

Published: Jan. 29, 2025

Leishmaniasis is one of the most important neglected tropical diseases, with more than two million new cases annually. It endemic in several regions worldwide, representing a public health problem for 88 countries, particular and subtropical developing countries. At moment, there are neither approved vaccines nor effective drugs treatment human leishmaniasis any its three typical clinical manifestations, and, importantly, use have side effects, require complex administration regimens, present high cost, ineffective many populations due to pathogen resistance. Moreover, beyond pharmacological exigencies, other challenges concerning parasitic nature, such as great genetic plasticity adaptability, enabling it activate battery genes develop resistance quickly. All these aspects demand identification development new, safe, chemical systems, which must not only be focused on medicinal chemistry but also consider key relative parasite survival. In this sense, quinolines particular, 4-aminoquinoline, represent privileged scaffold design potential leishmanicidal candidates their versatility generate highly active selective compounds correlation well-defined biological targets. These facts make possible safe agents targeted at The current review summarizes examples based 4-aminoquinolines focusing analysis essential aspects: (i) structure–property relationship identify pharmacophores (ii) mode action targets survival ( e.g. , depolarization mitochondrial, accumulation into macrophage lysosome, immunostimulation host cells). With that information, we seek give useful guidelines interested researchers face drug discovery process potent 4-aminoquinolines.

Language: Английский

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Synthesis and Mechanistic Insights of Coumarinyl-Indolinone Hybrids as Potent Inhibitors of Leishmania major

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117392 - 117392

Published: Feb. 1, 2025

Language: Английский

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Genetically Validated Drug Targets in Leishmania: Current Knowledge and Future Prospects

ACS Infectious Diseases, Journal Year: 2018, Volume and Issue: 4(4), P. 467 - 477

Published: Jan. 31, 2018

There has been a very limited number of high-throughput screening campaigns carried out with Leishmania drug targets. In part, this is due to the small suitable target genes that have shown by genetic or chemical methods be essential for parasite. perspective, we discuss state validation in field research and review 200 36 Trypanosoma cruzi which gene deletion attempts made since first published case 1990. We define quality score different techniques can used identify potential also how advances genome-scale disruption assist target-based phenotypic-based development other parasitic protozoa why lacked similar approach so far. The prospects scale work are considered context application CRISPR/Cas9 editing as useful tool Leishmania.

Language: Английский

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Benzophenone: a ubiquitous scaffold in medicinal chemistry

MedChemComm, Journal Year: 2018, Volume and Issue: 9(11), P. 1803 - 1817

Published: Jan. 1, 2018

Diaryl ketones are an important scaffold in drug discovery due to their prevalence naturally occurring bioactive compounds. This review discusses molecules containing the benzophenone moiety that have potent biological activity.

Language: Английский

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Route map for the discovery and pre-clinical development of new drugs and treatments for cutaneous leishmaniasis

International Journal for Parasitology Drugs and Drug Resistance, Journal Year: 2019, Volume and Issue: 11, P. 106 - 117

Published: June 20, 2019

Although there have been significant advances in the treatment of visceral leishmaniasis (VL) and several novel compounds are currently pre-clinical clinical development for this manifestation leishmaniasis, limited drug research (R & D) cutaneous (CL). Here we review need new treatments CL, describe vitro vivo assays, models approaches taken over past decade to establish a pathway discovery, drugs CL. These recent include mouse infection using bioluminescent Leishmania, introduction PK/PD skin infection, defined candidate profiles.

Language: Английский

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